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Cancers
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Cancers Gene Therapy
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Cancers Gene Therapy

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 October 2015) | Viewed by 51277

Special Issue Editor

Dr. Gabi Dachs

E-Mail Website
Guest Editor
Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand
Interests: ascorbate; cancer therapy; tumour hypoxia; hypoxia-inducible factors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer gene therapy is designed to destroy tumours via the delivery of therapeutic genes to malignant cells. Why has the hype surrounding cancer gene therapy not (yet) resulted in an approved therapy? Adverse tumour characteristics, including inadequate blood supply and high interstitial fluid pressure, make cancer cells in solid tumours difficult to access. An innovative approach, covering all complicated aspects of this therapy, is required to revive the field. After all, it still has the potential to be the most selective of all cancer treatments, able to target even distant cancer deposits whilst sparing normal tissue.
This special issue aims to bring together both original studies and reviews covering novel aspects of gene therapy of cancer. We specifically like to invite articles covering the following areas:

•    Novel therapeutic genes or gene/prodrug combinations
•    Novel gene delivery methods, including reports on progress in systemic delivery
•    Novel vectors, encompassing viral, bacterial, cellular and synthetic vectors
•    Expression targeting via transcriptional regulation
•    Targeting of not only tumour cells, but also stromal cells, including blood vessels and inflammatory cells
•    Direct comparisons of gene therapy to current clinical therapies
•    New imaging methods to determine location and extend of gene spread
•    Sophisticated cell culture models able to mimic tumour conditions
•    Sophisticated, and potentially humanised, animal models
•    Clinical trial design
•    Safety considerations and mechanisms of side effects
•    Results from early clinical trials and proof of concept reports
•    Patient and public perceptions of gene therapy of cancer

Dr. Gabi Dachs
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • therapeutic genes
  • vectors
  • expression targeting
  • stromal targeting
  • imaging
  • cell culture and animal models
  • clinical trials

Published Papers (7 papers)

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Research

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1542 KiB  
Article
Electrotransfer of Plasmid DNA Encoding an Anti-Mouse Endoglin (CD105) shRNA to B16 Melanoma Tumors with Low and High Metastatic Potential Results in Pronounced Anti-Tumor Effects
by Tanja Dolinsek, Gregor Sersa, Lara Prosen, Masa Bosnjak, Monika Stimac, Urska Razborsek and Maja Cemazar
Cancers 2016, 8(1), 3; https://doi.org/10.3390/cancers8010003 - 24 Dec 2015
Cited by 17 | Viewed by 5565
Abstract
Endoglin overexpression is associated with highly proliferative tumor endothelium and also with some tumors, including melanoma. Its targeting has anti-tumor effectiveness, which can also be obtained by RNA interference. The aim of our study was to explore the anti-tumor effectiveness of endoglin silencing [...] Read more.
Endoglin overexpression is associated with highly proliferative tumor endothelium and also with some tumors, including melanoma. Its targeting has anti-tumor effectiveness, which can also be obtained by RNA interference. The aim of our study was to explore the anti-tumor effectiveness of endoglin silencing by electrotransfer of plasmid DNA encoding short hairpin RNA against endoglin in two murine B16 melanoma variants with different metastatic potential on cells, spheroids and subcutaneous tumors in mice. The results demonstrate that endoglin silencing with gene electrotransfer reduces the proliferation, survival and migration of melanoma cells and also has anti-tumor effectiveness, as the therapy resulted in a high percentage of tumor cures (23% and 58% on B16F1 and B16F10 tumors, respectively). The effectiveness of the therapy correlated with endoglin expression in melanoma cells; in vitro the effects were more pronounced in B16F1 cells, which express more endoglin than B16F10. However, the opposite was observed in vivo in tumors, where there was a higher expression of endoglin and better anti-tumor effectiveness in the B16F10 tumor. In conclusion, targeting endoglin for the treatment of melanoma seems to be a concept worthy of further exploration due to the increased therapeutic effect of the therapy based on simultaneous vascular targeting and its direct effect on tumor cells. Full article
(This article belongs to the Special Issue Cancers Gene Therapy)
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561 KiB  
Article
New Variants of Tomato Thymidine Kinase 1 Selected for Increased Sensitivity of E. coli KY895 towards Azidothymidine
by Louise Slot Christiansen, Louise Egeblad, Birgitte Munch-Petersen, Jure Piškur and Wolfgang Knecht
Cancers 2015, 7(2), 966-980; https://doi.org/10.3390/cancers7020819 - 08 Jun 2015
Cited by 4 | Viewed by 4729
Abstract
Nucleoside analogues (NA) are prodrugs that are phosphorylated by deoxyribonucleoside kinases (dNKs) as the first step towards a compound toxic to the cell. During the last 20 years, research around dNKs has gone into new organisms other than mammals and viruses. Newly discovered [...] Read more.
Nucleoside analogues (NA) are prodrugs that are phosphorylated by deoxyribonucleoside kinases (dNKs) as the first step towards a compound toxic to the cell. During the last 20 years, research around dNKs has gone into new organisms other than mammals and viruses. Newly discovered dNKs have been tested as enzymes for suicide gene therapy. The tomato thymidine kinase 1 (ToTK1) is a dNK that has been selected for its in vitro kinetic properties and then successfully been tested in vivo for the treatment of malignant glioma. We present the selection of two improved variants of ToTK1 generated by random protein engineering for suicide gene therapy with the NA azidothymidine (AZT).We describe their selection, recombinant production and a subsequent kinetic and biochemical characterization. Their improved performance in killing of E. coli KY895 is accompanied by an increase in specificity for the NA AZT over the natural substrate thymidine as well as a decrease in inhibition by dTTP, the end product of the nucleoside salvage pathway for thymidine. The understanding of the enzymatic properties improving the variants efficacy is instrumental to further develop dNKs for use in suicide gene therapy. Full article
(This article belongs to the Special Issue Cancers Gene Therapy)
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Graphical abstract

824 KiB  
Article
Investigation of siRNA Nanoparticle Formation Using Mono-Cationic Detergents and Its Use in Gene Silencing in Human HeLa Cells
by Yuma Yamada, Ryosuke Suzuki and Hideyoshi Harashima
Cancers 2013, 5(4), 1413-1425; https://doi.org/10.3390/cancers5041413 - 01 Nov 2013
Cited by 4 | Viewed by 5911
Abstract
The focus of recent research has been on the development of siRNA vectors to achieve an innovative gene therapy. Most of the conventional vectors are siRNA nanoparticles complexed with cationic polymers and liposomes, making it difficult to release siRNA. In this study, we [...] Read more.
The focus of recent research has been on the development of siRNA vectors to achieve an innovative gene therapy. Most of the conventional vectors are siRNA nanoparticles complexed with cationic polymers and liposomes, making it difficult to release siRNA. In this study, we report on the use of MCD, a quaternary ammonium salt detergent containing a long aliphatic chain (L-chain) as an siRNA complexation agent using human HeLa cells (a model cancer cell). We prepared siRNA nanoparticles using various MCDs, and measured the diameters and zeta-potentials of the particles. The use of an MCD with a long L-chain resulted in the formation of a positively charged nanoparticle. In contrast, a negatively charged nanoparticle was formed when a MCD with a short L-chain was used. We next evaluated the gene silencing efficiency of the nanoparticles using HeLa cells expressing the luciferase protein. The results showed that the siRNA/MCD nanoparticles showed a higher gene silencing efficiency than Lipofectamine 2000. We also found that the efficiency of gene silencing is a function of the length of the alkyl chain in MCD and zeta-potential of the siRNA/MCD nanoparticles. Such information provides another viewpoint for designing siRNA vectors. Full article
(This article belongs to the Special Issue Cancers Gene Therapy)
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742 KiB  
Article
The Flavin Reductase MsuE Is a Novel Nitroreductase that Can Efficiently Activate Two Promising Next-Generation Prodrugs for Gene-Directed Enzyme Prodrug Therapy
by Laura K. Green, Mathew A. Storey, Elsie M. Williams, Adam V. Patterson, Jeff B. Smaill, Janine N. Copp and David F. Ackerley
Cancers 2013, 5(3), 985-997; https://doi.org/10.3390/cancers5030985 - 08 Aug 2013
Cited by 24 | Viewed by 7410
Abstract
Bacterial nitroreductase enzymes that can efficiently catalyse the oxygen-independent reduction of prodrugs originally developed to target tumour hypoxia offer great potential for expanding the therapeutic range of these molecules to aerobic tumour regions, via the emerging cancer strategy of gene-directed enzyme prodrug therapy [...] Read more.
Bacterial nitroreductase enzymes that can efficiently catalyse the oxygen-independent reduction of prodrugs originally developed to target tumour hypoxia offer great potential for expanding the therapeutic range of these molecules to aerobic tumour regions, via the emerging cancer strategy of gene-directed enzyme prodrug therapy (GDEPT). Two promising hypoxia prodrugs for GDEPT are the dinitrobenzamide mustard PR-104A, and the nitrochloromethylbenzindoline prodrug nitro-CBI-DEI. We describe here use of a nitro-quenched fluorogenic probe to identify MsuE from Pseudomonas aeruginosa as a novel nitroreductase candidate for GDEPT. In SOS and bacteria-delivered enzyme prodrug cytotoxicity assays MsuE was less effective at activating CB1954 (a first-generation GDEPT prodrug) than the “gold standard” nitroreductases NfsA and NfsB from Escherichia coli. However, MsuE exhibited comparable levels of activity with PR-104A and nitro-CBI-DEI, and is the first nitroreductase outside of the NfsA and NfsB enzyme families to do so. These in vitro findings suggest that MsuE is worthy of further evaluation in in vivo models of GDEPT. Full article
(This article belongs to the Special Issue Cancers Gene Therapy)
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Review

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2060 KiB  
Review
Advancing Clostridia to Clinical Trial: Past Lessons and Recent Progress
by Alexandra M. Mowday, Christopher P. Guise, David F. Ackerley, Nigel P. Minton, Philippe Lambin, Ludwig J. Dubois, Jan Theys, Jeff B. Smaill and Adam V. Patterson
Cancers 2016, 8(7), 63; https://doi.org/10.3390/cancers8070063 - 28 Jun 2016
Cited by 27 | Viewed by 7750
Abstract
Most solid cancers contain regions of necrotic tissue. The extent of necrosis is associated with poor survival, most likely because it reflects aggressive tumour outgrowth and inflammation. Intravenously injected spores of anaerobic bacteria from the genus Clostridium infiltrate and selectively germinate in these [...] Read more.
Most solid cancers contain regions of necrotic tissue. The extent of necrosis is associated with poor survival, most likely because it reflects aggressive tumour outgrowth and inflammation. Intravenously injected spores of anaerobic bacteria from the genus Clostridium infiltrate and selectively germinate in these necrotic regions, providing cancer-specific colonisation. The specificity of this system was first demonstrated over 60 years ago and evidence of colonisation has been confirmed in multiple tumour models. The use of “armed” clostridia, such as in Clostridium Directed Enzyme Prodrug Therapy (CDEPT), may help to overcome some of the described deficiencies of using wild-type clostridia for treatment of cancer, such as tumour regrowth from a well-vascularised outer rim of viable cells. Successful preclinical evaluation of a transferable gene that metabolises both clinical stage positron emission tomography (PET) imaging agents (for whole body vector visualisation) as well as chemotherapy prodrugs (for conditional enhancement of efficacy) would be a valuable early step towards the prospect of “armed” clostridia entering clinical evaluation. The ability to target the immunosuppressive hypoxic tumour microenvironment using CDEPT may offer potential for synergy with recently developed immunotherapy strategies. Ultimately, clostridia may be most efficacious when combined with conventional therapies, such as radiotherapy, that sterilise viable aerobic tumour cells. Full article
(This article belongs to the Special Issue Cancers Gene Therapy)
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800 KiB  
Review
Studies of Tumor Suppressor Genes via Chromosome Engineering
by Hiroyuki Kugoh, Takahito Ohira and Mitsuo Oshimura
Cancers 2016, 8(1), 4; https://doi.org/10.3390/cancers8010004 - 30 Dec 2015
Cited by 7 | Viewed by 8692
Abstract
The development and progression of malignant tumors likely result from consecutive accumulation of genetic alterations, including dysfunctional tumor suppressor genes. However, the signaling mechanisms that underlie the development of tumors have not yet been completely elucidated. Discovery of novel tumor-related genes plays a [...] Read more.
The development and progression of malignant tumors likely result from consecutive accumulation of genetic alterations, including dysfunctional tumor suppressor genes. However, the signaling mechanisms that underlie the development of tumors have not yet been completely elucidated. Discovery of novel tumor-related genes plays a crucial role in our understanding of the development and progression of malignant tumors. Chromosome engineering technology based on microcell-mediated chromosome transfer (MMCT) is an effective approach for identification of tumor suppressor genes. The studies have revealed at least five tumor suppression effects. The discovery of novel tumor suppressor genes provide greater understanding of the complex signaling pathways that underlie the development and progression of malignant tumors. These advances are being exploited to develop targeted drugs and new biological therapies for cancer. Full article
(This article belongs to the Special Issue Cancers Gene Therapy)
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584 KiB  
Review
Lentiviral Vectors for Cancer Immunotherapy and Clinical Applications
by Therese Liechtenstein, Noemi Perez-Janices and David Escors
Cancers 2013, 5(3), 815-837; https://doi.org/10.3390/cancers5030815 - 02 Jul 2013
Cited by 32 | Viewed by 10152
Abstract
The success of immunotherapy against infectious diseases has shown us the powerful potential that such a treatment offers, and substantial work has been done to apply this strategy in the fight against cancer. Cancer is however a fiercer opponent than pathogen-caused diseases due [...] Read more.
The success of immunotherapy against infectious diseases has shown us the powerful potential that such a treatment offers, and substantial work has been done to apply this strategy in the fight against cancer. Cancer is however a fiercer opponent than pathogen-caused diseases due to natural tolerance towards tumour associated antigens and tumour-induced immunosuppression. Recent gene therapy clinical trials with viral vectors have shown clinical efficacy in the correction of genetic diseases, HIV and cancer. The first successful gene therapy clinical trials were carried out with onco(g-)retroviral vectors but oncogenesis by insertional mutagenesis appeared as a serious complication. Lentiviral vectors have emerged as a potentially safer strategy, and recently the first clinical trial of patients with advanced leukemia using lentiviral vectors has proven successful. Additionally, therapeutic lentivectors have shown clinical efficacy for the treatment of HIV, X-linked adrenoleukodystrophy, and b-thalassaemia. This review aims at describing lentivectors and how they can be utilized to boost anti-tumour immune responses by manipulating the effector immune cells. Full article
(This article belongs to the Special Issue Cancers Gene Therapy)
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